| Abstrakt: |
The intestinal tract is a common site for various types of infections including viruses, bacteria, and helminths, each requiring specific modes of immune defense. The intestinal epithelium has a pivotal role in both immune initiation and effector stages, which are coordinated by lymphocyte cytokines such as IFNγ, IL-13, and IL-22. Here, we studied intestinal epithelial immune responses using organoid image analysis based on a convolutional neural network, transcriptomic analysis, and in vivo infection models. We found that IL-13 and IL-22 both induce genes associated with goblet cells, but the resulting goblet cell phenotypes are dichotomous. Moreover, only IL-13–driven goblet cells are associated with classical NOTCH signaling. We further showed that IL-13 induces the bone morphogenetic protein (BMP) pathway, which acts in a negative feedback loop on immune type 2–driven tuft cell hyperplasia. This is associated with inhibiting Sox4 expression to putatively limit the tuft cell progenitor population. Blocking ALK2, a BMP receptor, with the inhibitor dorsomorphin homolog 1 (DMH1) interrupted the feedback loop, resulting in greater tuft cell numbers both in vitro and in vivo after infection with Nippostrongylus brasiliensis. Together, this investigation of cytokine effector responses revealed an unexpected and critical role for the BMP pathway in regulating type 2 immunity, which can be exploited to tailor epithelial immune responses. BMP puts the brakes on tuft cells: Intestinal parasite infections or allergic reactions promote IL-13–induced differentiation of tuft cells as one manifestation of type 2 immunity in the gut. Using organoid cultures of intestinal epithelial cells, Lindholm et al. investigated how the lymphocyte cytokines IL-13, IL-22, and IFNγ regulate the signaling pathways that influence epithelial differentiation. While tuft cell IL-25 promoted expansion of IL-13–producing ILC2s in a feed-forward loop, the resulting IL-13 also induced ligands of the bone morphogenetic protein (BMP) signaling pathway. BMP agonists acted on stem cells to prevent runaway tuft cell expansion by limiting expression of Sox4, a transcription factor required for tuft cell differentiation. These findings provide new molecular insights into how intestinal epithelial differentiation is carefully choreographed in response to a diverse array of cytokine signals. [ABSTRACT FROM AUTHOR] |
